title: Expression of CD38 with intracellular enzymatic activity: a possible explanation for the insulin release induced by intracellular cADPR.
abstract: CD38 is a transmembrane glycoprotein expressed in multiple cell types, including pancreatic β cells. It can serve as an enzyme that catalyzes the metabolism of two different Ca(2+)-mobilizing compounds, cyclic adenosine diphosphoribose (cADPR) and nicotinic acid adenine dinucleotide phosphate. One of these metabolites, cADPR, is known to be involved in glucose-induced insulin secretion from pancreatic β cells. Although the essential role of CD38 for endogenous cADPR synthesis has been established, the relationship between the proposed extracellular enzymatic activity of CD38 and the intracellular Ca(2+) modulation caused by the intracellular cADPR accumulation has not yet been fully explained. For a better understanding of the role of CD38 in the insulin secretion machinery, analysis of the intracellular localization of this molecule in pancreatic β cells is essential. In an attempt to provide a method to probe the N-terminal and C-terminal of CD38 separately, we generated an insulin-secreting MIN6 murine pancreatic β cell line expressing a human CD38 bearing an N-terminal FLAG epitope tag. We found a weak but consistent expression of the FLAG epitope outside of the cells, indicating the presence of a small amount of CD38 with cytoplasmic enzymatic activity. MIN6 cells transfected with human CD38 exhibited increased glucose-induced insulin release. In addition, anti-FLAG cross-linking further enhanced the insulin release, suggesting that the N-terminal of CD38 expressed on the cell surface functions as a receptor for an unknown ligand and triggers positive signals for insulin secretion.
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ohta
authors.forename: Akira
authors.initials: A
authors.lastname: Kitanaka
authors.forename: Keichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Osamu
authors.initials: O
authors.lastname: Imataki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Terukazu
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taminato
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Kubota
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D018274:Electroporation; D005434:Flow Cytometry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice
chemical_list: D007328:Insulin; D036563:Cyclic ADP-Ribose; D051997:ADP-ribosyl Cyclase 1